The present invention relates to the use of anti-inflammatory agents to enhance the regeneration and healing of tissue (e.g. hard tissue and soft tissue).
Polymers comprising aromatic or aliphatic anhydrides have been studied extensively over the years for a variety of uses. For example, in the 1930s fibers comprising aliphatic polyanhydrides were prepared for use in the textile industry. In the mid 1950s, aromatic polyanhydrides were prepared with improved film and fiber forming properties. More recently, attempts have been made to synthesize polyanhydrides with greater thermal and hydrolytic stability and sustained drug release properties.
U.S. Pat. Nos. 4,757,128 and 4,997,904 disclose the preparation of polyanhydrides with improved sustained drug release properties from pure, isolated prepolymers of diacids and acetic acid. However, these biocompatible and biodegradable aromatic polyanhydrides have aliphatic bonds resulting in compounds with slow degradation times as well as relatively insoluble degradation products unless incorporated into a copolymer containing a more hydrophilic monomer, such as sebacic acid. The aromatic polyanhydrides disclosed in the ""128 Patent and the ""904 Patent are also insoluble in most organic solvents. A bioerodible controlled release device produced as a homogenous polymeric matrix from polyanhydrides with aliphatic bonds having weight average molecular weights greater than 20,000 and an intrinsic velocity greater than 0.3 dL/g and a biologically active substance is also described in U.S. Pat. No. 4,888,176. Another bioerodible matrix material for controlled delivery of bioactive compounds comprising polyanhydride polymers with a uniform distribution of aliphatic and aromatic residues is disclosed in U.S. Pat. No. 4,857,311.
Biocompatible and biodegradable aromatic polyanhydrides prepared from para-substituted bis-aromatic dicarboxylic acids for use on wound closure devices are disclosed in U.S. Pat. No. 5,264,540. However, these compounds exhibit high melt and glass transition temperatures and decreased solubility, thus making them difficult to process. The disclosed polyanhydrides also comprise radical or aliphatic bonds which cannot be hydrolyzed by water.
Polyanhydride polymeric matrices have also been described for use in orthopedic and dental applications. For example, U.S. Pat. No. 4,886,870 discloses a bioerodible article useful for prosthesis and implantation which comprises a biocompatible, hydrophobic polyanhydride matrix. U.S. Pat. No. 5,902,599 also discloses biodegradable polymer networks for use in a variety of dental and orthopedic applications which are formed by polymerizing anhydride prepolymers.
Biocompatible and biodegradable aromatic polyanhydrides have now been developed with improved degradation, processing and solubility properties, as well as therapeutic utilities. As demonstrated herein, the new aromatic polyanhydrides are particularly useful in enhancing regeneration and healing of tissue. Thus, these new polyanhydrides can be used in a variety of dental and orthopedic applications.
It has unexpectedly been discovered that the local administration of an anti-inflammatory agent to tissue provides beneficial effects on the healing and growth of the tissue and on proximally located tissues.
Accordingly, the invention provides a method to promote healing of tissue comprising administering an effective amount of an anti-inflammatory agent to or near the tissue.
The invention provides a method to promote healing of hard tissue comprising administering an effective amount of an anti-inflammatory agent to the hard tissue or to soft tissue near the hard tissue.
The invention also provides a method of treating periodontal disease comprising administering an effective amount of an anti-inflammatory agent at the site of the periodontal disease.
The invention also provides a method of treating a bone fracture comprising fixing the fracture with an orthopedic device comprising an anti-inflammatory agent.
The invention also provides a method to enhance regeneration of tissue comprising administering an effective amount of an anti-inflammatory agent to or near the tissue.
The invention also provides a method to enhance regeneration of hard tissue comprising administering an effective amount of an anti-inflammatory agent to the hard tissue or to soft tissue near the hard tissue.
The invention also provides a method to decrease bone resorption at a site in the body of a patient comprising administering an effective amount of an anti-inflammatory agent at or near the site.
The invention also provides a method to promote healing of bone comprising contacting the bone and surrounding soft tissue with an aromatic polyanhydride comprising a repeating unit having the structure: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is xe2x80x94Z1xe2x80x94R1xe2x80x94Z1xe2x80x94 substituted on each Ar ortho to the anhydride group, wherein R1 is a difunctional organic moiety and Z1 is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates so that regeneration of bone is enhanced.
The invention also provides a method of treating periodontal diseases in a patient comprising administering to the patient at the site of the periodontal disease an aromatic polyanhydride comprising a repeating unit having the structure: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is xe2x80x94Z1xe2x80x94R1xe2x80x94Z1xe2x80x94 substituted on each Ar ortho to the anhydride group, wherein R1 is a difunctional organic moiety and Z1 is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
The invention also provides a method of treating bone fractures in a patient comprising fixing the bone fracture with an orthopedic device comprised of or coated with an aromatic polyanhydride comprising a repeating unit having the structure: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is xe2x80x94Z1xe2x80x94R1xe2x80x94Z1xe2x80x94 substituted on each Ar ortho to the anhydride group, wherein R1 is a difunctional organic moiety and Z1 is a difunctional moiety selected from the group consisting of esters, amides, urethanes, carbamates and carbonates.
The invention also provides pharmaceutical compositions comprising an anti-inflammatory agent and a pharmaceutically acceptable carrier, which are formulated to provide controlled release of the agent at or near tissue (e.g. hard or soft tissue). Preferably, the compositions are formulated to provide local release of an effective amount of the agent over a period of at least about 2, about 5, about 10, about 20, or about 40 days. The compositions can also preferably be formulated to provide local release of an effective amount of the agent over a period of up to about 3 months, about 6 months, about 1 year, or about 2 years.
The preparation of aromatic polyanhydrides from ortho-substituted bis-aromatic carboxylic acid anhydrides disrupts the crystallinity of the resulting polymer, enhancing solubility and processability, as well as degradation properties. The use of hydrolyzable bonds such as esters, amides, urethanes, carbamates and carbonates as opposed to aliphatic bonds in these compounds further enhances these properties.
These aromatic polyanhydrides have a repeating unit within the structure of Formula I: 
wherein Ar is a substituted or unsubstituted aromatic ring and R is a difunctional organic moiety substituted on each Ar ortho to the anhydride group. Ar and R are preferably selected so that the hydrolysis products of the polyanhydrides have a the chemical structure of an anti-inflammatory agent, particularly salicylates such as aspirin, non-steroidal anti-inflammatory compounds, or other aromatic anti-inflammatory compounds. Ar is preferably a phenyl group and R is preferably xe2x80x94Z1xe2x80x94R1xe2x80x94Z1xe2x80x94 in which R1, is a difunctional moiety and both Z1s are independently either an ester xe2x80x94C(xe2x95x90O)Oxe2x80x94, amide xe2x80x94C(xe2x95x90O)Nxe2x80x94, anhydride xe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94, carbonate xe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94, urethane xe2x80x94Nxe2x80x94C(xe2x95x90O)xe2x80x94Nxe2x80x94, or sulfide xe2x80x94Sxe2x80x94 groups. R1 is preferably an alkylene group containing from 1 to 20 carbon atoms, or a group with 2-20 carbon atoms having a structure selected from (xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m, (CH2xe2x80x94CH2xe2x80x94CH2xe2x80x94Oxe2x80x94)m and (xe2x80x94CH2xe2x80x94CHCH3xe2x80x94Oxe2x80x94)m.
Ortho-substituted bis-aromatic carboxylic acid anhydrides of the present invention are used in the preparation of the aromatic polyanhydrides of the present invention. The ortho-substituted bis-aromatic carboxylic acid anhydrides have the structure of Formula II: 
wherein Ar and R, and the preferred species thereof, are the same as described above with respect to Formula I and R is substituted on each Ar ortho to the anhydride group.
The aromatic polyanhydrides of the present invention meet the need for moldable biocompatible biodegradable polymers and are particularly useful in enhancing the healing process of bone and surrounding soft tissue.
Accordingly, the present invention relates to compositions and methods of using compositions comprising a aromatic polyanhydride with a repeating unit of Formula I to enhance healing of tissue (e.g. hard tisue). It has been found that these compositions promote healing in hard tissue by inhibiting inflammation and/or pain in the surrounding soft tissues and by enhancing hard tissue regeneration by promoting growth and/or by reducing bone resorption. To use these compositions to enhance tissue regeneration, it is preferred that the compositions be incorporated into fibers, films, membranes, pastes or microspheres. For this use, it is also preferred that the compositions comprise poly(anhydride-esters), referred to herein as bioactive polyanhydrides that degrade into salicylic acid, an anti-inflammatory, antipyretic and analgesic agent. The hard tissue and surrounding soft tissue are directly contacted with the composition so that regeneration and healing is enhanced.
A more complete appreciation of the invention and other intended advantages can be readily obtained by reference to the following detailed description of the preferred embodiments and claims, which disclose the principles of the invention and the best modes which are presently contemplated for carrying them out.